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Neuronal GLP1R mediates liraglutide's anorectic but not glucose-lowering effect.

ABSTRACT: Glucose control and weight loss are cornerstones of type 2 diabetes treatment. Currently, only glucagon-like peptide-1 (GLP1) analogs are able to achieve both weight loss and glucose tolerance. Both glucose and body weight are regulated by the brain, which contains GLP1 receptors (GLP1R). Even though the brain is poised to mediate the effects of GLP1 analogs, it remains unclear whether the glucose- and body weight-lowering effects of long-acting GLP1R agonists are via direct action on CNS GLP1R or the result of downstream activation of afferent neuronal GLP1R. We generated mice with either neuronal or visceral nerve-specific deletion of Glp1r and then administered liraglutide, a long-acting GLP1R agonist. We found that neither reduction of GLP1R in the CNS nor in the visceral nerves resulted in alterations in body weight or food intake in animals fed normal chow or a high-fat diet. Liraglutide treatment provided beneficial glucose-lowering effects in both chow- and high-fat-fed mice lacking GLP1R in the CNS or visceral nerves; however, liraglutide was ineffective at altering food intake, body weight, or causing a conditioned taste aversion in mice lacking neuronal GLP1R. These data indicate that neuronal GLP1Rs mediate body weight and anorectic effects of liraglutide, but are not required for glucose-lowering effects.

SUBMITTER: Sisley S

PROVIDER: S-EPMC4038572 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Neuronal GLP1R mediates liraglutide's anorectic but not glucose-lowering effect.

Sisley Stephanie S Gutierrez-Aguilar Ruth R Scott Michael M D'Alessio David A DA Sandoval Darleen A DA Seeley Randy J RJ

The Journal of clinical investigation 20140424 6

Glucose control and weight loss are cornerstones of type 2 diabetes treatment. Currently, only glucagon-like peptide-1 (GLP1) analogs are able to achieve both weight loss and glucose tolerance. Both glucose and body weight are regulated by the brain, which contains GLP1 receptors (GLP1R). Even though the brain is poised to mediate the effects of GLP1 analogs, it remains unclear whether the glucose- and body weight-lowering effects of long-acting GLP1R agonists are via direct action on CNS GLP1R ...[more]

PMID: 24762441

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Project description:Abstract BACKGROUND: Glucagon-like peptide-1 (GLP-1) functions to increase insulin production in a glucose-dependent manner. Endogenous GLP-1 is rapidly degraded by the enzyme dipeptidyl peptidase 4 (DPP4), and GLP-1 receptor agonists and DPP4 inhibitors (DPP4Is) are now used in the treatment of diabetes. The GLP-1 receptor (GLP-1R) is a G-protein coupled receptor that is expressed widely, encoded for by GLP1R. The GLP1R variant rs6923761 (Gly168Ser) has been associated with increased weight loss in response to GLP-1 agonist therapy in some studies. This study tested the hypothesis that this variant would be associated with responsiveness to endogenous GLP-1 during DPP4I therapy. METHODS: Forty-seven subjects with hypertension and type 2 diabetes mellitus were assigned to one-week crossover therapy with placebo and the DPP4I sitagliptin (100 mg/d), and underwent a mixed meal study. Subjects were excluded for type 1 diabetes, poorly controlled diabetes with Hgb A1c ≥8.7%, use of an anti-diabetic medication other than metformin for last 12 months, or presence of secondary hypertension. RESULTS: Post-prandial GLP-1 levels were increased during sitagliptin (AUC 11413, 95% CI [7113, 15712]) as compared with placebo treatment (AUC 5101, 95% CI [2254, 7949], p<0.05), and did not significantly differ by genotype. Peak post-prandial glucose was significantly higher in placebo as compared with sitagliptin treatment (146.6 +/- 35.8 mg/dL versus 133.0 +/- 26.5 mg/dL, respectively; t=90 minutes, p<0.01). Subjects with one or two copies of the wild-type allele (Gly/Gly or Gly/Ser) had increased post-prandial glucose excursion as compared with Ser/Ser subjects, in both the placebo and sitagliptin treatments (plasma glucose at 90 minutes: placebo Gly/- 150.1 +/- 38.0 mg/dL vs Ser/Ser 132.6 +/- 13.7 mg/dL, p<0.05; sitagliptin Gly/- 135.8 +/- 27.3 mg/dL vs Ser/Ser 117.4 +/- 14.7 mg/dL, p<0.05). Post-prandial insulin levels were not different in the placebo versus sitagliptin treatments (AUC 13264, 95% CI [9296,17232] vs 11996, 95% CI [8278, 15714], respectively), but there was a genotype by drug treatment interaction (p<0.05) such that Ser/Ser subjects had higher post-prandial insulin in the placebo treatment as compared with other genotypes. This difference was eliminated with sitagliptin therapy. CONCLUSIONS: Homozygosity for the Ser variant of GLP1R is associated with decreased glucose after a mixed meal without altering the effect of sitagliptin on post prandial GLP-1 concentrations. Further studies are needed to assess whether this variant confers increased sensitivity at the GLP-1R and whether it affects the long-term response to DPP4I.

Project description:BackgroundAberrant sympathetic nerve activity exacerbates cardiovascular risk in hypertension and diabetes, which are common comorbidities, yet clinically sympathetic nerve activity remains poorly controlled. The hypertensive diabetic state is associated with increased reflex sensitivity and tonic drive from the peripheral chemoreceptors, the cause of which is unknown. We have previously shown hypertension to be critically dependent on the carotid body (CB) input in spontaneously hypertensive rat, a model that also exhibits a number of diabetic traits. CB overstimulation by insulin and leptin has been similarly implicated in the development of increased sympathetic nerve activity in metabolic syndrome and obesity. Thus, we hypothesized that in hypertensive diabetic state (spontaneously hypertensive rat), the CB is sensitized by altered metabolic signaling causing excessive sympathetic activity levels and dysfunctional reflex regulation.MethodsUsing a hypothesis-free RNA-seq approach, we investigated potential molecular targets implicated in energy metabolism mediating CB sensitization and its regulation of sympathetic outflow in experimental hypertension. Identified targets were characterized using molecular and functional techniques assessing peripheral chemoreflex sensitivity in situ and in vivo.ResultsWe discovered GLP1R (glucagon-like peptide-1 receptor) expression in the CBs of rat and human and showed that its decreased expression is linked to sympathetic hyperactivity in rats with cardiometabolic disease. We demonstrate GLP1R to be localized to CB chemosensory cells, while targeted administration of GLP1R agonist to the CB lowered its basal discharge and attenuated chemoreflex-evoked blood pressure and sympathetic responses. Importantly, hyperglycemia-induced peripheral chemoreflex sensitization and associated basal sympathetic overactivity were abolished by GLP1R activation in the CB suggesting a role in a homeostatic response to high blood glucose.ConclusionsWe show that GLP1 (glucagon-like peptide-1) modulates the peripheral chemoreflex acting on the CB, supporting this organ as a multimodal receptor. Our findings pinpoint CBs as potential targets for ameliorating excessive sympathetic activity using GLP1R agonists in the hypertensive-diabetic condition.

Project description:Background and objectivesPatients with diabetes mellitus inject insulin in different regions of the body. This study investigated the pharmacokinetic and pharmacodynamic properties of insulin degludec (IDeg), a new-generation once-daily basal insulin with an ultra-long duration of action, after subcutaneous (SC) administration in different injection regions.MethodsIn this study, 20 healthy subjects received single SC doses of IDeg (0.4 U/kg; separated by 13-21 days) in the thigh, abdomen and deltoid in a randomised, open-label, single-centre, single-dose, complete crossover trial. Each dose was followed by a 24-h euglycaemic clamp and 120-h pharmacokinetic blood sampling. The obtained pharmacokinetic/pharmacodynamic profiles were extrapolated to steady state by simulation using a pharmacokinetic/pharmacodynamic model.ResultsTotal IDeg exposure [area under the IDeg serum concentration-time curve 0-120 h after a single dose (AUCIDeg,0-120h,SD)] and maximum serum concentration [maximum IDeg serum concentration after a single dose (C max,IDeg,SD)] were higher (6-7 and 23-27 %, respectively) following a single SC dose in the deltoid or abdomen, compared with the thigh, as also observed with other insulin preparations. No statistical difference was observed in these measures between deltoid and abdominal administration. No pronounced differences were observed in the glucose-lowering effect of IDeg [area under the glucose infusion rate (GIR) curve 0-24 h after a single dose (AUCGIR,0-24h,SD) and maximum GIR after a single dose (GIRmax,SD)] when injected in the thigh, abdomen or deltoid (AUCGIR,0-24h,SD 2,572, 2,833 and 2,960 mg/kg, respectively). Simulated mean steady-state pharmacokinetic and pharmacodynamic profiles supported a flat and stable IDeg exposure and effect regardless of injection region, with comparable total glucose-lowering effects [area under the GIR curve at steady state (AUCGIR,τ,SS)] between the thigh, abdomen and deltoid.ConclusionsThese findings support administering IDeg SC in the thigh, upper arm or abdominal wall without affecting IDeg absorption or effect at steady state.

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Neuronal GLP1R mediates liraglutide's anorectic but not glucose-lowering effect.

Publications

Neuronal GLP1R mediates liraglutide's anorectic but not glucose-lowering effect.

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